KR20180125966A - Uses of Machitinip for the Treatment of Children with Amyotrophic Solitary Sclerosis - Google Patents

Abstract

The present invention provides a method for treating a patient suffering from non-aggressive or moderate agoraphylaxis (ALS), wherein the rate of change of the amyotrophic lateral sclerosis function assessment scale (ALSFRS-R) is <1.1 points / Wherein the method comprises administering a tyrosine kinase inhibitor or a mast cell inhibitor, particularly mastitinium, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one pharmaceutically active ingredient. .

Description

Uses of Machitinip for the Treatment of Children with Amyotrophic Solitary Sclerosis

The present invention provides a method for treating a patient suffering from non-aggressive or moderate agoraphylaxis (ALS), wherein the rate of change of the amyotrophic lateral sclerosis function assessment scale (ALSFRS-R) is <1.1 points / Administering a tyrosine kinase inhibitor or a mast cell inhibitor, particularly mastitinib, or a pharmaceutically acceptable salt or solvate thereof, in the form of a pharmaceutical composition, wherein the method is administered in combination with at least one pharmaceutically active ingredient The method comprising the steps of:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis reflecting the degeneration of motor neurons in the primary motor cortex, cortical vertebral track, brain stem and spinal cord (Wijesekera LC, et al. Orphanet J Rare Dis. 2009 Feb 3; 4: 3].

Approximately two-thirds of patients with typical ALS have a spinal cord-type disease (limb manifestation) and have symptoms associated with fatigue and localized muscle weakness that can be initiated either on the distal or proximal side, . In general, seizures can occur in weak atrophic limbs and can affect hand performance and walking. Patients with bulbous-onset ALS usually exhibit oral sleep disorders and dysphagia for solids or liquids. Limb symptoms develop almost simultaneously with bulbous symptoms, and most cases occur within one to two years. Paralysis is progressive and induces death by respiratory failure within 2 to 3 years in the case of bulbous onset and within 3 to 5 years in the case of respiratory-onset ALS.

Although most ALS cases are sporadic, 5 to 10% of cases are familial, 20% of them involve a mutation of the SOD1 gene (21q22.11), about 2 to 5% of TAR DNA-binding protein 43 (1p36.22) encoding the TARDBP gene encoding TDP-43, and 1-2% involves a mutation (9p13.3) of the VCP gene encoding the valine-containing protein. Apparently 2% of sporadic cases are accompanied by SOD1 mutations and TARDBP mutations are also identified in sporadic cases.

The cause of ALS is unclear, but some genetic risk factors have been identified. A recent review of the role of environmental risk factors in the cause of ALS concluded that there is no consistent relationship between a single environmental factor and the risk of developing ALS. Most authors support the hypothesis of complex genetic-environmental interactions as causative factors of motor neuron degeneration.

The exact molecular pathway that causes motor neuron degeneration in ALS is unclear, but as with other neurodegenerative diseases, it is likely to involve complex interactions between multiple pathogenic cell mechanisms that can not be mutually exclusive. These include genetic factors, excitotoxicity, oxidative stress, mitochondrial dysfunction, impaired axonal transport, neurofilament aggregation, protein aggregation, inflammatory dysfunction and non-neuronal cell contribution.

There is increasing evidence that inflammatory disorders and non-neuronal cells may play a role in the pathogenesis of ALS (Wijesekera LC, et al. Orphanet J Rare Dis. 2009 Feb 3; 4: 3]. Microglial and dendritic cell activation is a significant pathology in human ALS and transgenic SOD1 mice. These activated non-neuronal cells produce inflammatory cytokines such as interleukins, COX-2, TNF [alpha] and MCP-I, and evidence of upregulation is found in cerebrospinal fluid or spinal cord specimens of ALS patients or in vitro models. Neuroinflammation due to glial activation is now established as an important mode of pathology in ALS (Philips T, et al. Lancet Neurol. 2011; 10: 253-263. There is a significant activation or proliferation of both microglial and astrocytic cells in the human specific disease stage in vivo (Turner MR, et al. Neurobiol Dis 2004; 15: 601-9. There is also evidence of injury to all neurovascular unit elements, including blood-brain and blood-spinal cord barriers, in both patient and animal models of ALS (Garbuzova-Davis S. Amyotroph Lateral Scler. 2008 Dec; 9 (6): 375-6].

Another non-nerve cell that emerges is the mast cell. Mast cells are known to play a prominent role in all inflammatory processes by expressing receptors of molecules normally involved in such reactions. In addition, mast cells release a large variety of mediators that maintain inflammatory networks and regulate blood-brain barrier (BBB) permeability (Skaper SD, et al. Immunol 2014; 141: 314-327]. Significantly, mast cells and nerve cells are linked by activation of microglia in response to pro-inflammatory cytokines released from mast cells (Skaper SD, et al. Immunol 2014; 141: 314-327].

ALS patients have been observed in clinical practice to experience different rates of disease progression. It has been hypothesized that disease progression at different rates reflects the different etiologies of ALS, with effects on the efficacy of therapies for specific mechanisms of disease. In other words, heterogeneity within the entire ALS population with respect to disease progression can be explained by different subgroups of ALS patients.

There are at least two very different subpopulations of ALS patients within the entire ALS population, which may be referred to as " aggressive ALS " patients that progress at a relatively rapid rate, as measured through the progression of appropriate clinical markers of disease burden (Also referred to as " non-aggressive or moderately aggressive ALS ") that progresses at a relatively slow rate. The subgroup of electrons represents a more aggressive and heterogeneous form of the disease in patients with higher risk of death (significantly shorter median survival time) or in patients with tracheotomy [Kimura F, et al. Neurology 2006; 66: 265-267]. The latter group of "normal moderators" represents most of ALS patients.

No non-aggressive or moderately aggressive ALS or aggressive ALS is available to stop or reverse the progression of ALS progression. There has been no progress in the efficacy of available therapies over the past two decades since the registration of ALS's only approved drug, riluzole. Despite the fact that riluzole (100 mg) provides a modest survival benefit, not very significant improvement in function, it is an expensive drug and is estimated to cost approximately US $ 10,000 per patient per year in the United States.

A comprehensive review of Miller and colleagues on the use of riluzole for ALS has taken into account evidence of four randomized clinical trials involving 1477 ALS patients treated with ruruzole (Miller RG, et al. Cochrane Database Syst Rev. 2012 Mar 14; 3: CD001447]. The results of this meta-analysis indicate that riluzole 100 mg prolongs the median survival of ALS patients by 2 to 3 months in relation to participants taking placebo, and drug safety is not a major concern. There is no direct measurement of the quality of life from published trials. In addition, none of the randomized studies examined separately had beneficial effects of riluzole on patient function. There was a small beneficial effect on bulb and limb function only when the data were combined, but not on muscle strength; However, the authors warn that these functional outcomes should be interpreted with caution.

A number of symptomatic treatments that do not delay the progression of the disease but affect the quality of life are beneficial to the individual in clinical settings (Table 1 generally lists the various symptomatic treatments used in the management of ALS (see Jenkins TM , et al., Curr Opin Neurol, 2014 Oct; 27 (5): 524-31). However, evidence of significant benefit requires additional randomized clinical trials to provide a weaker and more robust evidence base. This comment has been reflected in the cork systematic review of the treatment of ALS's career by Ashworth and colleagues (published in 2006, updated in 2011) [Ashworth NL, et al. Cochrane Database of Systematic Reviews 2006, Issue 1 Art. No .: CD004156].

[Table 1]

Summary of symptomatic treatments commonly used in patients with ALS [Adopted from Jenkins 2014]

In conclusion, treatment of ALS is still a challenge for clinicians due to the diversity and complexity of the disease itself and the lack of standard and clinically meaningful effective therapies.

In addition, existing therapies do not consider the rate of disease progression, that is, non-aggressive or moderately aggressive ALS versus aggressive ALS.

A known approval or investigational drug does not indicate the cure of ALS. Moreover, the efficacy of known drugs is limited and may degrade over time with reports of undesirable side effects. Therefore, there is a continuing need to identify new drugs that have greater efficacy to treat ALS affecting most ALS patients, and particularly non-aggressive or moderately aggressive ALS.

Accordingly, the present invention provides a method of treating non-aggressive or moderately aggressive amyotrophic lateral sclerosis (ALS), comprising administering a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, optionally together with at least one pharmaceutically active ingredient And administering to the subject in need thereof.

The invention also relates to a method of treating non-aggressive or moderately aggressive ALS comprising administering an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, In combination with a pharmaceutically active ingredient, to a subject in need thereof.

It is an object of the present invention to solve the technical problem of providing an active ingredient for treating a patient suffering from non-aggressive or moderate aggressive ALS.

In one embodiment, the non-aggressive or moderately aggressive ALS is defined as having an Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score of less than 1.1 points per month prior to treatment initiation.

In another embodiment, the non-aggressive or moderately aggressive ALS is defined as a change rate of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline) is less than 1.1 points per month.

In one embodiment, the non-aggressive ALS is defined as the progression of the amyotrophic lateral sclerosis function assessment scale (ALSFRS-R) score before treatment initiation is less than 0.8 points per month. In another embodiment, the non-aggressive ALS is defined as the rate of change of the ALSFRS-R score from the first ALS-related symptom to the first treatment time (baseline) is less than 0.8 points per month.

In one embodiment, moderate aggressive ALS is defined as progression of the ALSFRS-R score before treatment initiation is less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month ). In another embodiment, the moderate aggressive ALS has a rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline) of less than 1.1 points per month and greater than or equal to 0.8 points per month &Lt; 1.1 points / month).

Accordingly, the present invention provides a method of treating a patient having a non-aggressive or moderately aggressive ALS (i. E., A patient having an ALSFRS-R score of less than 1.1 points per month prior to initiation of treatment), comprising a tyrosine kinase inhibitor, Comprising administering to a subject in need thereof an acceptable salt or solvate, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient, &Lt; / RTI &gt;

The present invention provides a method of treating a patient suffering from amyotrophic lateral sclerosis (ALS), wherein the progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month, comprising administering a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof Comprising administering to a subject in need thereof a combination of a pharmaceutically acceptable carrier, preferably mastitinium, or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than or equal to 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

The present invention relates to a method for the treatment of c-Kit, Lyn, Fyn, PDGFR, or a combination thereof for use in the treatment of patients with non-aggressive or moderately aggressive ALS (i.e., patients whose progression of the ALSFRS- And at least one tyrosine kinase selected from CSF1R or any combination thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof.

Thus, the present invention provides the use of c-Kit, Lyn, Fyn, PDGFR and CSFlR (SEQ ID NO: 1) for use in the treatment of patients suffering from amyotrophic lateral sclerosis (ALS) with progression of the ALSFRS- , Or any combination thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

The present invention also provides for the treatment of non-aggressive or moderately aggressive ALS, more particularly an active ingredient that improves prior art methods for the treatment of ALS patients whose progression of the ALSFRS-R score prior to treatment initiation is less than 1.1 points per month The objective is to solve the technical problem.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of at least one tyrosine selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, to be.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity. In another embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of microglial cell activity. In another embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity and microglial cell activity.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of mastocinib, imatinib, cromolyn sodium, midosutaurin, BLU-285, conservinib, iburutinib, LAS 189386 , DP-2618, tostamatinib, nilotinib, dasatinib, sunitinib, accitinib, pazopanib and toceranib.

In another embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of muscleinib, GW2580, plexidarnib, BLZ945, liniopanib, OSI-930, imatinib, From the group consisting of Nilotinib, Pazopanib, Eemartuuzumab, FPA008, Quizarthinib, Actinib, Mortesanib, Cediranip, JNJ-28312141, Ki-20227, MLN-518, Sorapanib and SU- Selected microglial cell inhibitor.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is a 2-aminoaryl thiazole derivative, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is mastitinib or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is masitinib mesylate.

Accordingly, the present invention provides a method for the treatment of non-aggressive or moderately aggressive ALS, wherein the progression of the ALSFRS-R score prior to treatment initiation is defined as less than 1.1 points per month, said method comprising administering to a human patient, Or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the method of the invention is for the treatment of a patient having an ALSFRS-R score of less than 0.8 points / month prior to initiation of treatment. In another embodiment, the method of the invention is for the treatment of a patient with an ALSFRS-R score of less than 1.1 points per month and greater than or equal to 0.8 points per month (&gt; 0.8 to &lt; 1.1 points per month) .

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with at least one pharmaceutically active ingredient. The pharmaceutically active ingredient is preferably active in the treatment of ALS. The pharmaceutically active ingredient is preferably an antglutamate compound, especially rylose (6- (trifluoromethoxy) benzothiazol-2-amine); Topiramate (2,3: 4,5-bis-O- (1-methylethylidene) -beta-D-fructopyranose sulfamate); Gabapentin (2- [1- (aminomethyl) cyclohexyl] acetic acid); (6- (2,3-dichlorophenyl) -1,2,4-triazine-3,5-diamine); 7-acetyl-5- (4-aminophenyl) -8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5- ] Benzodiazepine); (6R, 7R) -7 - [[(2Z) -2- (2- amino-1,3-thiazol-4-yl) -2- methoxyiminoacetyl] (2-methyl-5,6-dioxo-1H- 1,2,4-triazin-3-yl) sulfanylmethyl] -8-oxo-5-thia- 1- azabicyclo [4.2.0] Oct-2-en-2-carboxylic acid); Is an inhibitor of glutamate carboxypeptidase II. Preferably, the other pharmaceutically active ingredient is lyrusol.

The present invention aims to provide efficient treatment of non-aggressive or moderately aggressive ALS with appropriate dosing, route of administration and daily intake.

In one embodiment, the tyrosine kinase inhibitor, or a pharmaceutical salt or solvate thereof, preferably mastitinib, or a pharmaceutically acceptable salt or solvate thereof, and more preferably a mastitin mesylate, Orally.

In one embodiment, the tyrosine kinase inhibitor, or a pharmaceutical salt or solvate thereof, preferably mastitinib, or a pharmaceutically acceptable salt or solvate thereof, and more preferably a mastitin mesylate, Administered twice daily (i. E., Twice a day).

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutical salt or solvate thereof, preferably mastitinium, or a pharmaceutically acceptable salt or solvate thereof, and more preferably, The rate is administered in a daily dose ranging from about 1.0 to about 9.0 mg / kg (mg / kg body weight). In another embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutical salt or solvate thereof, preferably mastitinib, or a pharmaceutically acceptable salt or solvate thereof, and more preferably a muscle nib meal The dose is administered in a dose of 1.5, 3.0, 4.5, 6.0 or 7.5 mg / kg, more preferably at a dose of 3.0, 4.5 or 6 mg / kg / day (mg / kg body weight per day).

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of 3.0 mg / kg / day for at least 4 weeks followed by 4.5 mg / kg / day , And thereafter at a dose of 6.0 mg / kg / day, and each dose increase is provided for toxicity control.

The invention also relates to a tyrosine kinase inhibitor for use in the treatment of a non-aggressive or moderately aggressive ALS human patient wherein the progression of the ALSFRS-R score prior to initiation of treatment is less than 1.1 points per month as described herein, , Wherein the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is masitinib mesylate.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

In one embodiment, the tyrosine kinase inhibitor is administered in combination with the at least one pharmaceutically active ingredient in combination for simultaneous, separate or sequential use.

The present invention also relates to a tyrosine kinase inhibitor, preferably mastocinib, or a pharmaceutically acceptable salt or solvate thereof, as defined according to the invention, for use in the treatment of non-aggressive or moderately aggressive ALS will be.

The present invention also relates to pharmaceutical compositions comprising at least a pharmaceutically active ingredient, preferably an anti-glutamate compound, especially riluzole; Topiramate; Gabapentin; Lamotrigine; Taram panel; Ceftriaxone; In combination with an inhibitor of glutamate carboxypeptidase II, a tyrosine kinase inhibitor as defined according to the present invention, preferably mastocinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of non-aggressive or moderately aggressive ALS Salt or solvate thereof, and preferably said other pharmaceutically active ingredient is a lysoleol.

The present invention also provides a kit for the treatment of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, for use in a method of treatment of non-aggressive or moderately aggressive ALS defined according to the present invention , Preferably mastitinib, or a pharmaceutical salt or solvate thereof, for the manufacture of a medicament or kit.

In one embodiment, the pharmaceutical composition or medicament or kit of the present invention also comprises at least one other pharmaceutically active ingredient, preferably an anti-glutamate compound, especially riluzole; Topiramate; Gabapentin; Lamotrigine; Taram panel; Ceftriaxone; The inhibitor of glutamate carboxypeptidase II, and preferably the other pharmaceutically active ingredient is a lysoleol.

The invention also relates to a pharmaceutical composition comprising, optionally, at least one other pharmaceutical active ingredient, preferably an anti-glutamate compound, especially riluzole; Topiramate; Gabapentin; Lamotrigine; Taram panel; Ceftriaxone; Or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament or pharmaceutical composition for the treatment of non-aggressive or moderately aggressive ALS, in combination with an inhibitor of glutamate carboxypeptidase II, in combination with a tyrosine kinase inhibitor, Salt or solvate thereof, and preferably said other pharmaceutically active ingredient is a ruruzol as defined in the present invention.

The tyrosine kinase inhibitor and any at least one pharmaceutically active ingredient are administered in a dose regimen comprising a therapeutically effective amount.

Justice

In the present invention, the following terms have the following meanings:

As stated above, the expression " ALS patient with an ALSFRS-R score before initiation of treatment < 1.1 point per month " as used herein includes a subset of patients from the entire ALS patient population.

The term " ALSFRS-R score " refers to an amyotrophic lateral sclerosis functional assessment scale. ALSFRS-R is a score of 0 to 48 hours that evaluates the disability. ALSFRS-R includes 12 questions, each rated on a 5-point scale from 0 = disabled to 4 = normal. Individual item scores are summed to produce 0 = worst to 48 = best reported scores. The ALSFRS-R score correlates significantly with the quality of life measured by the staging profile, indicating that quality of function is a strong determinant of quality of life in ALS. [Cedarbaum JM. The ALSFRS-R: A revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999; 169: 13-21].

The term " progression of the ALSFRS-R score " refers to the rate of change of the ALSFRS-R score prior to treatment initiation, expressed in points per unit of time (e.g., months). As the disease progresses, the ALSFRS-R score decreases, that is, the rate of change of the ALSFRS-R score is a loss of points.

The " progress of the ALSFRS-R score " (point / month) is defined from the date of the first ALS- related symptom to the first treatment time (baseline). In other words, in one embodiment, the progression of the ALSFRS-R score prior to treatment initiation corresponds to the rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline). If the ALSFRS-R score is not known at the date of the first ALS-related symptom, the accepted estimate is to assign an upper limit of 48 hours (minimum disease burden).

The term " baseline " refers to the time immediately before randomization to treatment initiation or study.

The calculation of the " Progression of the ALSFRS-R score " for a given ALS patient is performed using the formula: {(ALSFRS-R score at the date of the first ALS-related symptom) / {(Time between first ALS-related symptoms and baseline)}. If the ALSFRS-R score is not known at the date of the first ALS-related symptom, the accepted estimate is to assign an upper limit of 48 hours (minimum disease burden).

The term " normal moderator " or " non-aggressive or moderately aggressive ALS " refers to a patient with an ALSFRS-R score of less than 1.1 points per month prior to initiation of treatment. Thus, patients with "normal moderators" or non-aggressive or moderately aggressive ALS have an ALSFRS-R score that decreases to less than 1.1 points per month. Among patients suffering from "normal host" or non-aggressive or moderately aggressive ALS, further distinction is possible:

- patients suffering from non-aggressive ALS with an ALSFRS-R score decreasing by less than 0.8 points / month (<0.8 points / month), and

Patients suffering from moderate aggressive ALS with an ALSFRS-R score of less than 1.1 points / month and decreasing by more than 0.8 points / month (≥ 0.8 to <1.1 points / month).

Both patients with non-aggressive ALS and those with moderate aggressive ALS were ALS patients with a progression of ALSFRS-R <1.1 points / month prior to initiation of treatment. In other words, ALS patients with an ALSFRS-R score of <1.1 points per month prior to initiation of therapy include both patients with non-aggressive ALS and those with moderate aggressive ALS.

The term " non-aggressive ALS " refers to a patient with an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. Thus, non-aggressive ALS patients have an ALSFRS-R score that decreases by less than 0.8 points per month.

The term " moderate aggressive ALS " refers to a patient with an ALSFRS-R score of less than 1.1 points per month and greater than or equal to 0.8 points per month (≥0.8 to <1.1 points per month) prior to treatment initiation. Thus, moderate aggressive ALS patients have an ALSFRS-R score that decreases by less than 1.1 points per month and by more than 0.8 points per month (≥0.8 to <1.1 points per month).

The term " early moderator " or " aggressive ALS " refers to a patient with an ALSFRS-R score of at least 1.1 points per month prior to treatment initiation. Thus, patients with "early moderators" or aggressive ALS have an ALSFRS-R score that decreases by 1.1 points per month or more.

The term " ALS patient with progression of ALSFRS-R prior to initiation of treatment < 1.1 points per month " may be used interchangeably with the expression " ALSFRS-R progression rate < 1.1 points / month prior to initiation of treatment &quot;.

The term " FVC " means mandatory vitality. FVC (percent predicted normal) is the measured vitality (VC) when the patient is breathing at maximum speed and effort. VC can be measured using a conventional spirometer with calibration check before testing.

The term " CAFS " refers to the combined assessment of function and survival (Berry JD et al., The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Apr; 14 (3): 162-8].

The term " overall survival " is defined as the time from randomization to clinical trial to documented death time.

The term " tracheal incisional survival " is defined as the time from randomization to clinical trial to documented death or first tracheostomy date.

The term " subject " refers to a mammal, preferably a human. In one embodiment, the subject may be a " patient &quot;, i.e. a warm-blooded animal, more preferably a human, who is awaiting receipt of medical care or is receiving medical care, is subject to medical procedures, Lt; / RTI &gt;

The term or "treatment", "treating" may refer to both therapeutic treatment and prognosis or prophylactic means, wherein the object is a non-aggressive or moderate intended to aggressively prevent ALS or extend (relief). Those in need of treatment include those that already have non-aggressive or moderately aggressive ALS, as well as those that are likely to have non-aggressive or moderate aggressive ALS, or non-aggressive or moderate aggressive ALS should be prevented. A subject exhibits a somewhat observable and / or measurable relief of one or more symptoms associated with non-aggressive or moderately aggressive ALS after the subject is provided with a therapeutic amount of a tyrosine kinase inhibitor according to the present invention; &Quot; treated " for non-aggressive or moderately aggressive ALS when it indicates a reduced rate of mortality and mortality, and an improvement in the quality of life problems. The parameter is easily measurable by a normal procedure familiar to a physician.

The term " marcitinib " also designates its acceptable salts or solvates, especially marcinate nisylate, unless explicitly stated otherwise.

The term " as defined in accordance with the present invention " encompasses any preferred embodiment and variations and includes any embodiment and feature relating to a tyrosine kinase inhibitor, preferably muscleinib, a method of treatment of non-aggressive or moderately aggressive ALS Refers to any embodiment or aspect of the invention, alone or in combination without limitation, including pharmaceutical compositions, pharmaceutical compositions, and other pharmaceutically active ingredient (s), preferably any combination with ryuzole.

The term " therapeutically effective amount " refers to an amount of a compound that, without causing a significant negative or adverse or adverse effect on the target, (1) delays or prevents the onset of non-aggressive or moderately aggressive ALS; (2) delay or halt the progression, aggravation or degradation of one or more symptoms of non-aggressive or moderately aggressive ALS, (3) result in the improvement of symptoms of ALS; (4) reduce the severity or occurrence of non-aggressive or moderately aggressive ALS; (5) the level or amount of an agent intended to heal non-aggressive or moderately aggressive ALS. Therapeutically effective doses may be administered prior to the onset of non-aggressive or moderately aggressive ALS for prophylactic or cognitive function. Alternatively or additionally, a therapeutically effective amount can be administered after the onset of non-aggressive or moderately aggressive ALS for therapeutic or maintenance therapy.

The term " pharmaceutically acceptable carrier or excipient " refers to an excipient or carrier which, when administered to an animal, preferably a human, does not produce a deleterious, allergic or other undesirable reaction. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, the injected preparation should meet the aseptic, fumigant, general safety and purity criteria required by, for example, the FDA Office or EMA.

The term " solvate " is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules.

The word " about & quot ; preceding the number means +/- 10% of the above value.

As used herein, the term " aryl group " refers to a monocyclic or polycyclic-aromatic radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups are phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8- But are not limited to, tetrahydronaphthyl. The aryl group may be unsubstituted or substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring contains 6 carbon atoms, referred to herein as " (C6) aryl &quot;.

As used herein, the term " alkyl group " means a saturated straight or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; Saturated branched alkyl is a saturated or unsaturated, branched or cyclic, branched or cyclic, monovalent, branched or cyclic, monovalent, branched or cyclic, monovalent, branched or cyclic, Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, Dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl 3-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3-diethylhexyl, and the like. The alkyl groups included in the compounds of the present invention may be optionally substituted with one or more substituents.

As used herein, the term " alkoxy " refers to an alkyl group attached to another moiety by an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy and the like. The alkoxy group may be optionally substituted with one or more substituents.

The term " heteroaryl " or the like, as used herein, refers to a monocyclic or polycyclic heteroaromatic ring containing a carbon atom ring member and one or more heteroatom ring members (e.g., oxygen, sulfur or nitrogen) it means. Typically, the heteroaryl group has from 1 to 5 heteroatom ring members and from 1 to about 14 carbon atom ring members. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo [1,3] dioxolyl, benzo [1,4] dioxinyl, Thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl , Benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyryl Pyridyl, pyrrolo [2,3] pyrimidinyl, pyrazolo [3,4] pyrimidinyl, imidazo [1,2-a] pyridyl and benzo (b) . The heteroatom may be substituted with a protecting group known to those skilled in the art, for example, hydrogen on the nitrogen may be substituted with a tert-butoxycarbonyl group. The heteroaryl group may be optionally substituted with one or more substituents. In addition, nitrogen or sulfur heteroatom ring members may be oxidized. In one embodiment, the heteroaromatic ring is selected from a 5-8 membered monocyclic heteroaryl ring. The point of attachment of a heteroaromatic or heteroaryl ring to another group can be in either a carbon atom or a heteroatom of a heteroaromatic or heteroaryl ring.

The term " heterocycle " as used herein collectively refers to a heterocycloalkyl group and a heteroaryl group.

The term " heterocycloalkyl & quot ;, as used herein, refers to a monocyclic or bicyclic heterocycle which has at least one heteroatom selected from O, N or S and which has from 2 to 11 carbon atoms and which may be saturated or unsaturated, Means a polycyclic group. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidinyl, Wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, alkynyl, alkynyl, alkynyl, Tetrahydrothiopyranylsulfoxide, tetrahydrothiopyranylsulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl- , Tetrahydrothienyl, and tetrahydro-1,1-dioxothienyl. Typically, monocyclic heterocycloalkyl groups have from 3 to 7 members. Preferred 3- to 7-membered heterocycloalkyl groups are those having 5 or 6 ring atoms. The heteroatom may be substituted with a protecting group known to those skilled in the art, for example, hydrogen on the nitrogen may be substituted with a tert-butoxycarbonyl group. In addition, the heterocycloalkyl group may be optionally substituted with one or more substituents. The point of attachment of the heterocyclic ring to another group may also be present in either the carbon atom or the heteroatom of the heterocyclic ring. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.

As used herein, the term "substituent" or "substituted" is a compound or a hydrogen radical on the group, the protective group is substantially stable, any desired groups of the reaction conditions using the protective group when the form or protected &Lt; / RTI &gt; Examples of preferred substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); Alkyl; Alkenyl; Alkynyl; Hydroxy; Alkoxy; Nitro; Thiol; Thioether; immigrant; Cyano; Amido; Phosphoneate; Phosphine; Carboxyl; Thiocarbonyl; Sulfonyl; Sulfonamide; Ketones; Aldehyde; ester; Oxygen (-O); Haloalkyl (e.g., trifluoromethyl); Cycloalkyl which may be monocyclic or fused or unfused polycycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclic which may be monocyclic or fused or non-fused polycyclic, Cycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, Wherein R is selected from the group consisting of pyridyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, Pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl or benzofuranyl); Amino (primary, secondary or tertiary); CO ₂ CH ₃ ; CONH ₂ ; OCH ₂ CONH ₂ ; NH ₂ ; SO ₂ NH _2; OCHF ₂ ; CF _3; OCF ₃ ; This moiety may also be optionally substituted by a fused-ring structure or bridge, for example, -OCH ₂ O-. These substituents may be further substituted with substituents selected from this group. In certain embodiments, the term "substituent" or adjective "substituted" refers to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, _{-C (O) NR 11 R 12} , -NR 13 C (O) R 14, halo, -OR _13, cyano, nitro, _{haloalkoxy, -C (O) R 13,} -NR 11 R 12, -SR _{13, -C (O) OR 13} , -OC (O) R 13, -NR 13 C (O) NR 11 R 12, -OC (O) NR 11 R 12, -NR 13 C (O) OR 14, -S (O) consisting of _{r R 13, -NR 13 S (} O) r R 14, -OS (O) r R 14, S (O) r NR 11 R 12, -O, -S , and -NR ₁₃ Refers to a substituent selected from the group, wherein r is 1 or 2; R ₁₁ and R ₁₂ are each independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl; R ₁₁ and R ₁₂ together with the nitrogen to which they are attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R ₁₃ and R ₁₄ are each independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, Aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl. In certain embodiments, the term " substituent " or adjective &quot; substituted &quot; refers to a solubilization group.

The term " solubilising group " means any group that can be substantially ionized and render the compound soluble in the desired solvent, e.g., water or water-containing solvent. In addition, the solubilization group may be one that increases the affinity of the compound or complex. Typically, the solubilization group is selected from alkyl groups substituted with one or more heteroatoms, such as N, O, or S, and each is independently substituted with alkoxy, amino, alkylamino, dialkylamino, carbonyl, cyano Lt; / RTI &gt; alkyl group, or is substituted by cycloheteroalkyl or heteroaryl, or by a phosphate or sulfate or carboxylic acid. For example, " solubilization group &quot; refers herein to one of the following:

An alkyl, cycloalkyl, aryl, heteroaryl group containing at least one nitrogen or oxygen heteroatom and the group being substituted by at least one amino group or oxo group;

Saturated moieties which may be substituted by a group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl An amino group which may be a click amino group;

- one of the structural formulas a) to i) below (wherein the dashed line and the arrow line correspond to the attachment point for the core structure of the formula [A]).

The term " cycloalkyl &quot; means a saturated cyclic alkyl radical having from 3 to 10 carbon atoms. Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The cycloalkyl group may be optionally substituted with one or more substituents.

The term " halogen " means -F, -Cl, -Br or -I.

Accordingly, the present invention provides a method for treating non-aggressive or moderately aggressive amyotrophic lateral sclerosis (ALS) in a subject, preferably a human patient, comprising administering a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, To a subject or patient in need thereof. Preferably, a therapeutically effective amount of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject.

In one embodiment, non-aggressive or moderately aggressive ALS in the patient is diagnosed by calculation of the ALSFRS-R score for the patient. The calculation of the progression of the ALSFRS-R score for a given ALS patient is carried out using the formula: {(ALS SFRS-R score at baseline) + ALSFRS-R score at baseline (Time between first ALS-related symptoms and baseline). If the ALSFRS-R score is not known at the date of the first ALS-related symptom, the acceptable value is to replace the 48 hour upper limit (minimum disease burden).

Thus, in one embodiment, the progression of the ALSFRS-R score prior to treatment initiation corresponds to the rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline).

Patients with an ALSFRS-R score of less than 1.1 points / month prior to initiation of therapy are defined as "normal moderators" who are suffering from non-aggressive or moderately aggressive ALS. Thus, a patient with a " normal moderator ", i.e. a progression of the ALSFRS-R score before initiation of therapy is less than 1.1 points per month (< 1.1 points per month)

- Patients suffering from non-aggressive ALS with an ALSFRS-R score of less than 0.8 points per month (<0.8 points per month) prior to treatment initiation, and

Patients with moderate aggressive ALS with a progression of the ALSFRS-R score before initiation of treatment less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month).

Thus, in one embodiment, the non-aggressive or moderately aggressive ALS is defined as the progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month. In another embodiment, the non-aggressive or moderately aggressive (ALS) is defined as the rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline) is less than 1.1 points per month.

In one embodiment, the non-aggressive ALS is defined as the progression of the ALSFRS-R score before treatment initiation is less than 0.8 points per month. In another embodiment, the non-aggressive ALS is defined as the rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline) is less than 0.8 points per month.

In one embodiment, the moderate aggressive ALS is defined as the progression of the ALSFRS-R score before treatment initiation is less than 1.1 points per month and greater than 0.8 points per month (≥ 0.8 to <1.1 points per month). In another embodiment, the moderate aggressive ALS has a rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the first treatment time (baseline) of less than 1.1 points per month and greater than or equal to 0.8 points per month &Lt; 1.1 points / month).

If the ALSFRS-R score is not known at the date of the first ALS-related symptom, the acceptable value is to replace the 48 hour upper limit (minimum disease burden).

ALSFRS-R is a score of 0 to 48 hours that evaluates instability. ALSFRS-R includes 12 questions, each rated on a 5-point scale from 0 = disabled to 4 = normal. Individual item scores are summed to produce a reported score between 0 = worst to 48 = best. The ALSFRS-R score correlates significantly with the quality of life as measured by the staging profile, indicating that quality of function is a strong determinant of quality of life in ALS (Cedarbaum JM. J Neurol Sci 1999; 169: 13-21).

The ALSFRS-R is a rapidly administered (5 minute) sequential assessment scale (Rating 0-4) used to determine the evaluation of the subject's ability and independence in 12 functional activities / questions. All 12 activities are related to ALS. The initial validity was established by demonstrating that the ALSFRS-R score was correlated with a change in the age-related intensity in ALS patients, further measuring quality of life and predicting survival (Traynor B, et al. , Neurology, 2004.63: 1933-35]. Test-retest reliability exceeds 0.88 for all test items. The advantage of ALSFRS-R is that the category is related to ALS, and the device is an agile and reliable tool for assessing the activity of ALS patients' daily activities and is quickly managed. ALSFRS-R performs the appropriate training and can be managed with high inter-rater reliability and test / retest reliability.

The ALSFRS-R 12 questions and their assessment scales are as follows:

ALSFRS-R device

1. Speaking

Make sure the subject is recording the change in speaking. The subject compares his / her current function to the function before any symptoms of ALS.

4 Conventional speaking process

Speaking is the condition of the stage before the onset of the disease. If the object is speaking perfectly normal, the class 4

3 Detectable speaking difficulties

Some detectable changes in speech

Can be understood as two iterations

A little repetition is needed to understand speaking.

1 Speaking in combination with non-voice communication

Gestures, including hand gestures or head nudity, or speaking combined with communication aids, including low or high technical devices, are needed to communicate

0 Loss of useful speaking

It is not possible for an object to communicate verbally

2. Salivary secretion

The current status versus the status before ALS is assessed, regardless of whether the subject is receiving saliva for salivation. The current state includes all dosages or treatments used.

4 Normal

3 Slight, but clear excess saliva from mouth; Saliva can be shed at night.

2 moderate excess saliva; At least saliva can be shed.

1 A small amount of saliva

0 Significant saliva flow

Need a certain tissue or handkerchief

3. Swallowing

4 Normal diet

Swallow without difficulty, can eat arbitrary food or liquid.

3 Premature Eating Problem - Sometimes Moment

The subject is asked to avoid any food because it is caught in his / her throat; You can still eat all your choice food, but occasionally it is a gem.

2 Meal Consistency Change

It is necessary to avoid certain foods or change the consistency of foods.

1 Supplementary tube supply is required.

0 NPO

Exclusive parenteral or enteral feeding

4. Handwriting

The question is asked about dominant hand writing prior to ALS onset without using any ancillary equipment, such as using foam tubing and / or mechanical aids for hand or finger weakness.

4 Normal

3 Slow or messy; All words are readable.

2 All words can not be read.

One word can not be read, but you can still catch the pen.

0 Pen can not be caught.

5a. Food cutting and equipment handling

In patients without gastrectomy

Note: If> 50% of the nutrients are from g-tubes, use 5b.

If the subject chooses not to cut food or self-support for any reason, he / she is assessed as not capable. No ability is evaluated as zero.

4 Normal

There is no difficulty in cutting or handling tools by the method used before the onset of the disease

3 It is a little slow, but it does not need help.

It is somewhat difficult to cut or manipulate the tools by the method used before the onset of the disease, but the subject continues to perform independently.

2 Slow and steady but can cut most foods (> 50%) and need some help.

Some difficulty in cutting or handling tools by the methods used before the onset of the disease; The subject needs assistance, but still attempts to cut some food, and still performs> 50% of the work successfully.

1 Food should be cut by someone, but still eat food slowly.

The patient can not cut food by the method used before the onset of the disease, but still attempts to eat his / her own food and at least occasionally succeeds.

0 I need to feed.

5b. Food cutting and tool handling

In patients without gastrectomy

Note: The 5b option is only used if the subject does not have a gastrectomy and it is the primary method of eating. If the subject has a prior gastrectomy but takes most of their nutrition (more than 50%) orally, use 5a until 5b is the appropriate choice. The response to question 5b refers to tube-ingestion procedures and manipulations.

4 Normal

3 It is searchable, but all operations can be performed independently.

2 Closures and fasteners need some help.

1 Provide minimum support to caregivers.

0 You can not perform any aspect of the operation.

6. Dressing and hygiene

If the subject chooses not to dress himself or bathe himself for any reason, he / she is assessed as not capable. No ability is evaluated as zero.

4 Normal function

The patient does not involve difficulty and is still completely independent of dressing and hygiene in the manner used before disease onset.

3 Independent; Efforts can be made to complete self-management with reduced efficiency.

The patient is still completely independent in dressing, but requires more effort to dress; There is no alternative to wearing clothes.

2 Intermittent Auxiliary and Alternative Methods

Patients may have occasional support or use of ancillary equipment or alternative methods of dressing and hygiene (eg, pulling clothes, velcro closures or shoes, shirts with pre-buttoned pants, lying down on pants, use of shower stools or benches) in need.

1 Self-management requires a performer.

The average object requires daily caregiver support for dressing, but the subject has some function.

0 full dependency

7. Back-to-bed and sleepwear adjustment

If the subject chooses not to lie down in bed or adjust his pajamas for any reason, he / she is assessed as having no ability. The ability to perform sheep activity, turn around and sleepwear adjustments is rated as 3 or 4. Performing one activity is rated as 2.

4 Normal function

3 It is somewhat slow and crawling, but does not need help.

The patient may use a railing, a headboard, or an electric bed.

2 Can be turned back alone or adjust the seat, but it is very difficult.

The patient can turn back alone or adjust the sheet, but it is very difficult to complete the task; No help was needed. The patient may use a railing, a headboard, or an electric bed.

1 You can start, but you can not turn around or adjust your seat alone.

0 Power

8. Walking

Definition of a walk defined by an object.

4 Normal

3 difficult to walk

There are some difficulties, but I walk without assistance.

Walk with 2 assistants

AFO, walking stick, pedestrian or caregiver.

1 Only functional movement that can not be walked

The patient can partially move the limb for functional exercise; Can stand and can support weight for movement, but can not walk.

0 Intentional leg workout

9. Stair climbing

If the object chooses not to climb the stairs for any reason, he / she is evaluated as " 0- not possible ".

4 Normal

3 Slow

2 Instability or fatigue of hardness

The patient needs rest between steps or feels unstable, but does not need a rail.

1 assistance is required.

The patient requires assistance, including handrails or caregivers; Aids are needed for stability and safety.

Can not be 0

ALSFRS-R Respiratory Subscale

10. Difficulty breathing

4 None

3 Occurs when walking.

2 Occurs in one or more of the following: meals, bathing, dressing

1 Occurs during rest: Dyspnea when sitting or lying down

0 Significant Difficulties: Reviewing the Use of Mechanical Respiration Support

11. Tidal breathing

When using BiPAP overnight, it is evaluated as 0, and the subject can not sleep without the device. If the subject uses BiPAP but occasionally sleeps without the device (can sleep without the device), select the device that best represents the subject's respiration when sleeping without the device.

4 None

3 Some sleeping difficulties at night due to shortening of respiration usually do not use more than two pillows.

2 You need extra pillows (more than two) to sleep.

1 I have to sit and sleep.

0 I can not sleep without mechanical assistance.

12. Respiratory failure

4 None

3 Intermittent use of BiPAP

Continuous use of BiPAP for 2 nights

Continuous use of BiPAP for one week and night

Invasive mechanical ventilation by intubation or tracheostomy

Thus, there are at least two very different subpopulations of ALS patients within the entire ALS population, which are referred to as " early host " patients (also referred to as " aggressive ALS ") whose progression of ALSFRS- ); And "normal host" patients (also referred to as "non-aggressive or moderately aggressive ALS") whose progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month. The former group of diseases represents a more aggressive and heterogeneous form of the disease in patients with high mortality risk (significantly shorter median survival time) or tracheostomy (Kimura F, et al. Neurology 2006; 66: 265-267]. Among patients suffering from "normal host" or non-aggressive or moderately aggressive ALS, further distinction is possible:

- patients suffering from non-aggressive ALS with an ALSFRS-R score of less than 0.8 points per month (<0.8 points per month), and

Patients suffering from moderate aggressive ALS with an ALSFRS-R score of less than 1.1 points per month and greater than 0.8 points per month (≥0.8 to <1.1 points per month).

Tyrosine kinases are receptor type or non-receptor type proteins, which transduce the terminal phosphate of ATP to the tyrosine residue of the protein to activate or inactivate the signal transduction pathway. These proteins are known to be involved in a number of cellular mechanisms, and in the case of disruption, this leads to disorders such as abnormal cell proliferation and migration and further inflammation. Thus, in the sense of the present invention, " tyrosine kinase inhibitors " are drugs that inhibit tyrosine kinases and interfere with intracellular signal transduction processes. Blocking this process can stop cell growth and cleavage.

In one embodiment, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of non-aggressive or moderately aggressive ALS in a subject of the invention comprises a wild-type c-Kit, Lyn, Fyn, PDGFR And an inhibitor of CSF1R kinase activity, or any combination thereof. In yet another embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a wild-type c-Kit, Lyn, Fyn, PDGFR and (I. E., These tyrosine kinases or tyrosine kinase receptors contribute to possible tyrosine kinase inhibitor cardiac toxicity including ABL, KDR and Src) (Dubreuil et al., 2009, PLoS ONE 2009.4 9): e7258] [Davis et al., Nat Biotechnol 2011,29 (11): 1046-51].

In one embodiment, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, for use in the methods of the invention may thus induce cell cycle arrest and apoptosis of cell lines that are dependent on c-Kit signaling [Dubreuil et al., 2009, PLoS ONE, 4 (9): e7258]. Stem cell factors, ligands of c-Kit receptors are important growth factors in mast cells; Thus, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, for use in the methods of the present invention is an effective anti-mast cell and has direct anti-proliferative properties against mast cells through inhibition of c-Kit signaling and Pro-apoptosis. Similarly, Lyn and Fyn kinases are known to play important roles in the transduction pathway leading to IgE-induced degranulation of mast cells; Thus, tyrosine kinase inhibitors or pharmaceutically acceptable salts or solvates thereof for use in the methods of the present invention modulate the activation of mast cells through the targeting of Lyn and Fyn.

Mast cells themselves play an important role in maintaining the inflammatory network of the central nervous system, and mast cell-microglia crosstalk further contributes to maintaining the inflammatory response.

Mast cells are characterized by their differentiation at the functional and histochemical levels as well as the location and structure of the tissues. Activation of mast cells is accompanied by controlled release of various mediators essential to the defense of organisms against invading pathogens. Mast cells produce a variety of different mediators that fall into three groups here:

- preformed granules - associated parameters (histamine, proteoglycan and neutral protease);

Lipid-derived mediators (prostaglandins, thromboxanes and leukotrienes);

- Various cytokines (interleukins: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and tumor necrosis factor alpha TNF- MIP-1 [beta] and IFN- [gamma]).

Human mast cells constitutively express multiple receptors for different biological molecules. Of these receptors that induce the activation of mast cells in the ligation, the most known is the high affinity receptor (FcεRI) of IgE. Binding of the IgE-polyvalent antigen complex to Fc? RI leads to receptor aggregation and internalization, signal transduction and degranulation. This involves the transcription of the cytokine gene and thus can persist the inflammatory response. Moreover, induction of mast cells can be induced by various pre-formed and / or transfected cells, such as vasoactive amines (histamine, serotonin), sulfated proteoglycans, lipid mediators (prostaglandin D2, leukotrienes), growth factors, proteases, cytokines and chemokines, / Or induces the secretion of the newly synthesized mediator. These mediators produce a complex inflammatory response by synergy, either alone or with macrophage-derived and T cell-derived cytokines, leading to the mobilization and activation of inflammatory cells to the degranulation site.

Mast cells are found on both sides of the BBB and also have the ability to cross the BBB rapidly, thereby increasing their number in response to physiological stimulation (Nautiyal K, et al. Proc Natl Acad Sci USA. 2008 November; 18; 105 (46): 18053-18057 [Theoharides TC, et al. J Neuroimmunol. 2004 Jan; 146 (1-2): 1-12] (Silverman AJ, et al. J Neurosci 2000, 20: 401-408]. Release of these pro-inflammatory mediators into the central nervous system may alter the function of both nerve and vascular elements (Skaper SD, et al. Immunol 2014; 141: 314-327]. The ligands of the stem cell factor, c-Kit receptor, are important growth factors of mast cells. Similarly, Lyn and Fyn kinases are known to play important roles in the transduction pathway leading to IgE-induced degranulation of mast cells; Thus, c-Kit, Lyn, and Fyn are targets to regulate mast cell activity.

Thus, in one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity.

In one embodiment, the inhibitor of mast cell activity is imatinib (STI571, Novartis), more preferably imatinib mesylate. Thus, in a particular embodiment, the invention provides a method of treating non-aggressive or moderately aggressive ALS in mammals, and in particular in human patients, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of: imatinib (STI571, CGP57148B): 4 - [(4-methyl-1-piperazinyl ) Methyl] -N- (4-methyl-3 - {[4- (3-pyridinyl) -2-pyrimidinyl] amino} phenyl) benzamide as an effective amount of a compound known in the art . The preparation of such compounds is described in Example 21 of EP 564 409, a particularly useful form being described in WO 99/03854.

In another embodiment, the inhibitor of mast cell activity is selected from the group consisting of midostotin (PKC412; Novartis), bastisinib (BMS354825; Bristol-Myers Squibb), suinitinib (SU11248; Pfizer), nilotinib (AMN107; Pfizer, AG0013736, GlaxoSmithKline, SU11654, Pfizer, BLU-285 (Blueprint Medicines), SKI-606 (Pfizer), ibrutinip (PCI-32765 Pharmacyclics, Almirall R & D Center, DP-2618 (Deciphera Pharmaceuticals), Fostamatibip (R788) and Cromolyn sodium.

In another embodiment, the inhibitor of mast cell activity is selected from the group consisting of mastitinib, imatinib, cromolyn sodium, midosutaurin, BLU-285, conservinib, iburutinib, LAS 189386, DP-2618, Dasatinib, sunitinib, acacitinium, pazopanib and toceranib.

CSF-1, which is derived from neurons through CSF-1R, is recognized as a mechanism that causes microglial proliferation in the spinal cord. Damaged motor neurons were observed to induce spinal cord microglia expansion by expressing CSF-1 (Guan Z, et al. (2016) Nature Neuroscience 19 (1): 94-101]; Thus, CSF-1R is a target for regulating microglial activity. In addition, microglia respond to pro-inflammatory signals emitted from non-nerve cells (mainly those of immune origin, such as mast cells). Evidence indicates that there is extensive communication between the immune system and the central nervous system and that proinflammatory cytokines play an important role in this communication (Skaper SD, et al. Immunol 2014; 141: 314-327]. Thus, mast cell-microglial crosstalk further enhances and extends the effect of chronic neuroinflammation.

Tyrosine kinase inhibitors, or pharmaceutically acceptable salts or solvates thereof, for use in the methods of the present invention also modulate the activation of microglial cells by their targeting of CSF-1R.

Thus, in one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of microglial cell activity.

In one embodiment, the inhibitor of said microglial cell activity is selected from the group consisting of GW2580 (GlaxoSmithKline), Plexidarnib (PLX3397; Plexxikon), BLZ945 (Novartis), LINIPANIP (ABT- 869; Abbott), OSI- INC.), Imatinib (STI571, Novartis), SUNITINIP (SU11248; Pfizer), AMN107 (Novartis), GlaxoSmithKline, EGATSU, Roche, FPA008 (Five Prime Therapeutics, AstraZeneca, JNJ-28312141 (Johnson & Co., Inc.), AC220 (Daiichi Sankyo), Actinib (AG-013736; Pfizer), motesanib (AMG- Johnson), Ki-20227 (Kirin Pharma Company Limited), MLN-518 (Millennium), Sorapenib (Bayer) and SU-14813 (Pfizer).

In yet another embodiment, the inhibitor of microglial cell activity is selected from the group consisting of muscleinib, GW2580, plexidarnib, BLZ945, liniopanib, OSI-930, imatinib, suminitinib, nitorinib, pazopanib, May be selected from Zymap, FPA008, quizarthinib, axitinib, motesanib, cediranib, JNJ-28312141, Ki-20227, MLN-518, sorapenib and SU-14813.

In addition, there is extensive communication between the immune system and the central nervous system via, for example, mast cells, and proinflammatory cytokines play an important role in this communication (Skaper SD, et al. Immunol 2014; 141: 314-327]. The obtained mast cell-microglial crosstalk further enhances and extends the effect of chronic neuroinflammation; Thus, tyrosine kinase inhibitors or pharmaceutically acceptable salts or solvates thereof for use in the methods of the present invention also modulate nerve inflammation through the inhibition of mast cell-microglial crosstalk.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity and microglial cell activity.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is a 2-aminoaryl thiazole derivative.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is a 2-aminoaryl thiazole derivative of formula (A) In another embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is a 2-aminoaryl thiazole derivative of formula (B)

In one embodiment, a tyrosine kinase for use in a method of treatment of non-aggressive or moderately aggressive ALS in a subject of the invention (i. E., A human patient of ALS with a progression of ALSFRS-R score prior to initiation of therapy is less than 1.1 points per month) The inhibitor or a pharmaceutically acceptable salt or solvate thereof has the formula (A)

(A)

In the above formula (A)

R ₁ and R ₂ are independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl group having 1 to 10 carbon atoms, trifluoromethyl, alkoxy, cyano, dialkylamino and solubilization groups,

m is 0-5,

n is 0-4;

Group R &lt; ₃ &gt; is one of the following:

(i) aryl, such as phenyl or substituted variants thereof, comprising any combination of at least one substituent, such as halogen, alkyl groups of 1 to 10 carbon atoms, trifluoromethyl, cyano, and alkoxy, group;

(ii) a heteroaryl group such as a 2,3 or 4-pyridyl group, which may additionally contain any combination of one or more substituents such as halogen, an alkyl group having 1 to 10 carbon atoms, trifluoromethyl and alkoxy, ;

thienyl, 3-thienyl, 2-thienyl, 2-thienyl, 2-thienyl, 2-thienyl, 2-thienyl, 5-membered aromatic heterocyclic group such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like.

In one embodiment, a tyrosine kinase inhibitor for use in a method of treatment of non-aggressive ALS in a subject (i. E., A human patient of ALS with an ALSFRS-R score of less than 0.8 points / month prior to treatment initiation) Lt; RTI ID = 0.0 &gt; A &lt; / RTI &gt;

In one embodiment, a tyrosine kinase inhibitor for use in a method of treatment of moderately aggressive ALS in a subject (i. E., A human patient of ALS with an ALSFRS-R score progression of &gt; 0.8 to &Lt; RTI ID = 0.0 &gt; A &lt; / RTI &gt;

In certain embodiments, a tyrosine kinase inhibitor or a medicament for use in a method of treatment of non-aggressive or moderately aggressive ALS in a subject (i. E., A human patient of ALS having a progression of ALSFRS-R score of less than 1.1 points / Acceptable salt or solvate thereof has the formula (B)

[Chemical Formula B]

In the above formula (B)

R ₁ is independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl of 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino,

m is 0-5.

In certain embodiments, a tyrosine kinase inhibitor for use in a method of treatment of non-aggressive ALS in a subject of the present invention (i. E., A human patient of ALS having an ALSFRS-R score of less than 0.8 points / Lt; RTI ID = 0.0 &gt; B &lt; / RTI &gt;

In certain embodiments, a tyrosine kinase inhibitor for use in a method of treatment of moderately aggressive ALS in a subject of the invention (i. E., A human patient of ALS with a progression of ALSFRS-R score before initiation of therapy is? 0.8 to &Lt; RTI ID = 0.0 &gt; B &lt; / RTI &gt; as hereinbefore defined.

Pharmaceutically acceptable salts include, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic acids or sulfonic acids such as, for example, fatty acid mono- or di-carboxylic acids, Such as acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid or amino acids such as arginine or lysine, aromatic carboxylic acids such as benzoic acid , 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids such as nicotinic acid or isonicotinic acid, Aliphatic sulfonic acids such as methane-, ethane- or 2-hydroxyethanesulfonic acid, especially methanesulfonic acid, or aromatic sulfonic acids such as benzene-, p-toluene- or naphthalene- Pharmaceutically acceptable acid addition salts with &lt; RTI ID = 0.0 &gt; ene-2-sulfonic &lt; / RTI &gt;

Unless otherwise specified, reference to "mesylate" is used herein to refer to a salt of methanesulfonic acid with a named pharmaceutical substance (eg, a compound of formula A or B). The use of a mesylate other than mesylate has been shown to be effective in the treatment of INNM (modified World), which is granted by WHO (eg World Health Organization (February 2006), International Nonproprietary Names Modified. INN Working Document 05.167 / General name). For example, masitinib or imitinib mesylate refer to the methanesulfonate of masitinib and imitinib, respectively.

In one very preferred embodiment, the tyrosine kinase inhibitor of Formula B for use in the methods of the present invention is masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate.

Preferably, " masitinib mesylate " is an oral bioavailable mesylate salt of masitinib -CAS 1048007-93-7 (MsOH); C ₂₈ H ₃ O N ₆ OS.CH ₃ SO ₃ H; MW means 594.76:

CH₃SO₃H

CH ₃ SO ₃ H

The chemical name of masticipine is 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- It is number 790299-79-5.

Machitinib is described in US 7,423,055 and EP 1 525 200 B1. Detailed procedures for the synthesis of marcitinib mesylate are given in WO 2008/098949.

Tyrosine kinase inhibitors, preferably tyrosine kinase inhibitors of formula A or B, or muscinib mesylate can preferably be used as inhibitors of the wild type c-Kit, Lyn, Fyn, PDGFR and CSF1R kinase activity or any combination thereof .

In the context of the present invention, it is believed that, although not wishing to be bound by theory, it is believed that the c-Kit / SCF signaling pathway and thus the ability to inhibit the survival and / or activation of mast cells or to inhibit mast cell degranulation and thus mast cell- Molecules capable of modulating crosstalk or capable of inhibiting the CSF-1 / CSF-1R signaling pathway and thus of microglial proliferation, or any combination thereof, can modulate the symptoms and progression of ALS. In particular with respect to the present invention, tyrosine kinase inhibitors, in particular muscovidin, as defined above, can be used for the treatment of non-aggressive or moderately aggressive ALS &lt; RTI ID = 0.0 &gt; , Particularly in the treatment of patients with an ALSFRS-R score of less than 1.1 points per month prior to initiation of treatment, including but not limited to reducing total mast cell load, inhibiting total activity of mast cells, Play a role in suppressing torque and inhibiting microglia proliferation and thus affecting the overall inflammatory cascade. Unexpectedly, although not intending to be bound by theory, through this multifunctional mechanism, the use of tyrosine kinase inhibitors according to the present invention can induce a response in non-aggressive or moderately aggressive ALS patients.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

The present invention relates to a method for the treatment of non-aggressive or moderately aggressive ALS in a human patient, wherein said method comprises administering a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, especially mastitinium, or a pharmaceutically acceptable salt or solvate thereof, Solvate to a human patient in need thereof.

In the context of the present invention, non-aggressive or moderately aggressive ALS in human patients is defined as the progression of the ALSFRS-R score prior to treatment initiation to less than 1.1 points per month. According to the present invention, non-aggressive ALS in human patients is further defined as having an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. According to the present invention, moderate aggressive ALS in human patients is further defined as the progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month and greater than 0.8 points per month (≥ 0.8 to <1.1 points per month).

Accordingly, the present invention relates to a method of treating a patient suffering from amyotrophic lateral sclerosis (ALS) wherein the progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month.

The present invention also relates to a method for the treatment of patients suffering from amyotrophic lateral sclerosis (ALS), wherein the progression of the ALSFRS-R score prior to treatment initiation is less than 1.1 points per month, from c-Kit, Lyn, Fyn, PDGFR and CSF1R At least one tyrosine kinase inhibitor selected, or any combination thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to the use of c-Kit, Lyn, Fyn, PDGFR and / or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients suffering from amyotrophic lateral sclerosis (ALS), wherein the progression of the ALSFRS- CSF1R, or any combination thereof, preferably mastitinib, or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the patient has an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the patient has an ALSFRS-R score of less than 1.1 points / month and greater than 0.8 points / month (≥0.8 to <1.1 points / month) before initiation of treatment.

In the context of the present invention, the term " treatment " (and its various grammatical forms) refers to the prevention, healing, reversing, attenuating, alleviating, or preventing the deleterious effects of disease states, disease progression, , Minimizes, inhibits, or stops the operation. For example, treatment may include alleviation of symptoms of the disease (i. E., Not necessarily all symptoms) or attenuation of disease progression.

The present inventors have surprisingly found that marcitabine provides a therapeutic benefit to very different subpopulations of ALS patients in which the progression of the ALSFRS-R score prior to treatment initiation serves as an independent predictor of therapeutic efficacy.

A randomized placebo-controlled Phase 3 study (AB10015) was conducted to compare the efficacy and safety of marucinate in combination with riluzole in the treatment of patients suffering from ALS with placebo combined with ruruzole 1).

In accordance with the prospectively declared AB10015 study interim analysis, the present inventors have surprisingly found that, in a subset of ALS, caseinib produces a clinical benefit when compared to placebo (see Example 2). These subgroups, defined as limited eligibility criteria, consisted of ALS patients, and the progression of the ALSFRS-R score before treatment initiation was less than 1.1 points per month; Aggressive or moderately aggressive ALS subgroup or " normal modulator " subgroup of the entire ALS population, including patients suffering from non-aggressive ALS or moderate aggressive ALS as defined above. This result represents new knowledge and could not be predicted by teaching from the prior art.

Macit nip showed improvement in placebo at the primary endpoint (P = 0.0032, Table 4), indicating a statistically significant delay in disease progression. This positive treatment effect was unexpectedly found to be strongly induced by non-aggressive or moderately aggressive ALS subgroups (P = 0.0004, Table 5), and aggressive ALS (defined above (P = 0.4327, Table 6). The incidence of Mastitinib in patients with early or moderate progression was limited or not. Taken together, these data demonstrate that muscleinib produces clinical benefits in a limited population of non-aggressive or moderately aggressive ALS (normal host), unexpectedly superior to other patient cohorts. These findings support the use of the progression of the ALSFRS-R score (threshold of less than 1.1 points per month) prior to initiation of treatment as an independent predictor of patient selection for maxillofacial therapy efficacy from the entire ALS population.

Thus, the present inventors have surprisingly found that an individual subgroup responds to Machitinib therapy and the distinction is less than 1.1 points per month of study (baseline) (non-aggressive ALS and moderately aggressive ALS as defined herein above) Group) of the ALSFRS-R score from the date of the first ALS-related symptom to the randomization time, which is based on the aggressiveness of the disease, calculated from the rate of change of the ALSFRS-R score, It can be generalized by the progress of the score.

The method of the present invention has been found to advantageously provide a significantly beneficial effect on non-aggressive or moderately aggressive ALS patients (normal host). In one embodiment, the expression " normal moderator " or " non-aggressive or moderately aggressive " means that the treated patient suffering from ALS has a history of disease progression expressed in the progression of the ALSFRS- Quot; clinical &lt; / RTI &gt;

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with at least one pharmaceutically active ingredient. The pharmaceutically active ingredient is preferably active in the treatment of ALS.

Examples of pharmaceutically active ingredients include, but are not limited to, antiglutamate compounds, particularly ryluzole (6- (trifluoromethoxy) benzothiazol-2-amine); Topiramate (2,3: 4,5-bis-O- (1-methylethylidene) -beta-D-fructopyranose sulfamate); Gabapentin (2- [1- (aminomethyl) cyclohexyl] acetic acid); (6- (2,3-dichlorophenyl) -1,2,4-triazine-3,5-diamine); 7-acetyl-5- (4-aminophenyl) -8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5- ] Benzodiazepine); (6R, 7R) -7 - [[(2Z) -2- (2- amino-1,3-thiazol-4-yl) -2- methoxyiminoacetyl] (2-methyl-5,6-dioxo-1H- 1,2,4-triazin-3-yl) sulfanylmethyl] -8-oxo-5-thia- 1- azabicyclo [4.2.0] Oct-2-en-2-carboxylic acid); And inhibitors of glutamate carboxypeptidase II.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an anti-glutamate compound.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with ruruzole.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R or any combination thereof And is administered in combination with riluzole.

In one embodiment, the inhibitor of mast cell activity of the present invention is administered in combination with ruruzole. In one embodiment, the inhibitor of microglial cell activity of the present invention is administered in combination with riluzole.

The present invention also provides a method of treating non-aggressive or moderately aggressive ALS in a subject, preferably a human patient, comprising administering to a patient in need of such treatment a combination of mastitin, or a pharmaceutically acceptable salt or solvate thereof, To a subject or patient in need thereof.

In one embodiment, the method of the invention is for the treatment of a patient having an ALSFRS-R score of less than 0.8 points per month prior to treatment initiation. In another embodiment, the method of the invention is for the treatment of a patient with an ALSFRS-R score of less than 1.1 points per month and greater than 0.8 points per month (&gt; 0.8 to &lt; 1.1 points per month) .

Riluzole may be administered twice daily at a dose of 50 to 200 mg / day, for example, 50, 100 or 200 mg / day, preferably 50 mg.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with topiramate.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with gabapentin.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with lomotrichine.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with tamrampanel.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with ceftriaxone.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an inhibitor of glutamate carboxypeptidase II.

In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutical salt or solvate thereof, is administered simultaneously, separately or sequentially with at least one pharmaceutically active ingredient.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutical salt or solvate thereof, is administered in combination with the at least one pharmaceutically active ingredient as a combination preparation for simultaneous, separate or sequential use.

In connection with the best dose regimen, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, especially mastitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the methods of the present invention, Should be administered in a daily dose ranging from about 9.0 mg / kg / day (mg / kg body weight / day). In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutical salt or solvate thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably a mastitonin mesylate About 1.5 to about 7.5 mg / kg / day; For example, about 1.5, about 3.0, about 4.5, about 6.0 or about 7.5 mg / kg / day, more preferably about 3.0, about 4.5 or about 6.0 mg / kg / day (mg / &Lt; / RTI &gt;

Nevertheless, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, particularly mastitinib or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 7.5 mg / kg / day, more preferably about 4.5 Or an increment of about 1.5 mg / kg / day in a low-response patient to reach a maximum of about 6.0 mg / kg / day. Each increment of capacity is provided for toxicity control in the absence of any toxic event that would result in a dose escalation.

In one embodiment, the increase in the capacity of the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is achieved after at least 4 weeks of administration of the first dose and after the first dose of 26 weeks, such as 4 Week, 8, 12, 16, 20 or 24 weeks prior to administration. Each dose escalation was provided for toxicity control, including, but not limited to, a 4-week treatment period at a fixed dose of the study protocol, no suspected serious adverse events were reported, and suspected adverse events did not induce discontinuation And suspected adverse events are not initiated at the time of dose escalation regardless of their severity. In the absence of any of the toxic events described above, a certain capacity increase may occur. In the case of dose escalation without treatment reduction at the time of treatment resumption, or in the case of non-serious suspected adverse events in progress at the treatment interruption time, any dose escalation is delayed until after the additional 4 weeks treatment period. Capacity escalation is not available for patients who have had a dose reduction for safety reasons.

In one embodiment, a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of 3 mg / kg / day, followed by a dose of 4.5 mg / kg / day for 6 weeks, followed by a dose of 4.5 mg / kg / day, preferably twice daily. In another embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, is initially administered at a dose of 3.0 mg / kg / day, followed by a dose of 4.5 mg / kg / day, preferably twice a day.

In another example, mastitinib or a pharmaceutically acceptable salt or solvate thereof is initially administered at a dose of 3 mg / kg / day for 4 weeks, 4.5 mg / kg / day for 4 weeks, and then 6 mg / / kg / day, preferably twice a day, with each dose being provided for toxicological control.

In one embodiment, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably a mastitin mesylate Is initially administered at a dose of 4.5 mg / kg / day for at least 6 weeks, followed by 6.0 mg / kg / day for at least 6 weeks and then 6.0 mg / kg / day, with each dose being provided for toxicological control.

Any dose disclosed herein refers to the amount of active ingredient per se and is not in its salt form.

When the mg / kg / day of muscinib dose used as the described dose regimen refers to the amount of active ingredient muscleinib, the compositional change in the pharmaceutically acceptable salt of the muscleinib mesylate will change the dose regimen Do not.

In certain embodiments, maxillipine or a pharmaceutically acceptable salt or solvate thereof may be administered further via different routes of administration, although oral administration is preferred. In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered orally. In one embodiment, a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered twice a day by ingestion. Thus, in still another preferred embodiment, in said use or method, mastitinib or a salt or solvate thereof is administered orally; Preferably over 6 months, preferably over 12 months, for a long period of time. Mastitinib or a pharmaceutically acceptable salt or solvate thereof may be administered in the form of 100 and 200 mg tablets.

In one embodiment, a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably mastitonib mesylate, In an amount of at least 50 mg and less than 600 mg, preferably at least 100 mg and less than 400 mg.

The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor of the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to a medicament comprising a tyrosine kinase inhibitor of the invention or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a kit comprising a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the pharmaceutical compositions, medicaments or kits of the present invention comprise masitinib or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the pharmaceutical composition, medicament or kit of the present invention comprises a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one pharmaceutically active ingredient. In one embodiment, the pharmaceutical compositions, medicaments or kits of the invention comprise a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, together with at least one other pharmaceutically active ingredient, preferably an anti-glutamate Compounds, especially ryluzole; Topiramate; Gabapentin; Lamotrigine; Taram panel; Ceftriaxone; In combination with an inhibitor of glutamate carboxypeptidase II, and preferably the other pharmaceutically active ingredient is a lysoleol.

In one embodiment, the pharmaceutical compositions, medicaments or kits of the invention comprise a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, together with at least one anti-glutamate compound and / or a glutamate carboxypeptidase II &lt; / RTI &gt; inhibitors. In one embodiment, a pharmaceutical composition, medicament, or kit of the invention comprises a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one compound selected from the group consisting of riluzole, topiramate, gabapentin, And at least one other pharmaceutically active ingredient selected from the group consisting of salicylic acid, palnell, and ceftriaxone.

In one embodiment, a pharmaceutical composition, medicament, or kit of the present invention comprises a tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with ruruzole. In a preferred embodiment, the medicament or kit of the present invention comprises masitinib, or a pharmaceutically acceptable salt or solvate thereof, in combination with ruruzole.

According to a particular embodiment, the pharmaceutical composition or medicament of the present invention is thus an oral composition.

As is known to those skilled in the art, various forms of excipients suitable for the mode of administration may be employed, some of which may, for example, facilitate the release profile so that the active molecule as a whole is more effective for the desired treatment The effect of the active molecule can be promoted.

Thus, the pharmaceutical compositions, medicaments or compositions for use in the methods of the present invention may be administered in a variety of forms, such as, for example, in injectable, powderable or ingestible forms such as intramuscular, intravenous, subcutaneous , Intradermal, oral, topical, rectal, vaginal, ophthalmic, intranasal, transdermal or parenteral routes. A preferred route is oral administration.

The invention encompasses the use of compounds according to the invention, in particular for the preparation of pharmaceutical compositions or medicaments.

Such pharmaceutical or pharmaceutical compositions may take the form of pharmaceutical or pharmaceutical compositions suitable for oral administration and may be formulated using pharmaceutically acceptable carriers known in the art as suitable dosages. Such a carrier makes it possible to formulate a pharmaceutical composition into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for ingestion by a patient. In addition to the active ingredients, these pharmaceutical compositions may comprise suitable pharmaceutically acceptable carriers, including excipients and adjuvants, which facilitate the processing of the active compounds with pharmaceutically usable formulations. Further details of techniques for formulation and administration can be found in the current edition of Remington ' s Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

Example

The present invention is further illustrated by the following examples.

Example 1

Research AB10015

design:

Study AB10015 is a prospective, multicenter, randomized, double-blind, placebo-controlled study designed to compare the efficacy and safety of placebo in combination with raluzole in combination with marucinib versus luruzole in the treatment of patients with amyotrophic lateral sclerosis (ALS) - blind, placebo-controlled, force group, phase 2/3 study.

Randomization:

381 patients were randomized into three groups:

Group 1: 127 patients received 4.5 mg / kg / day of Machitinib plus lyrisol.

Group 2: 127 patients received 3 mg / kg / day of Machitinib plus lyrisol.

Group 3: 127 patients received placebo plus lyrisol.

Subgroup analysis (subgroup of ALS patients):

There are two different populations of ALS patients: the subgroup of the "normal host" and the subgroup of the "early host". The targeting population for the primary analysis is a subgroup of the "normal moderator".

Population of "normal host":

A " normal moderator " is defined as an ALS patient whose progression of the ALSFRS-R score before randomization is less than 1.1 points per month. This population represents approximately 80% of ALS patients.

Population of "normal moderator + early moderator":

The population of "normal moderators + early moderators" includes all ALS patients, "normal moderators" ALS patients, or "early moderators" ALS patients. An "early facilitator" is defined as an ALS patient with an ALSFRS-R score before randomization of at least 1.1 points per month.

Key inclusion criteria :

- Female or male patients were between 18 and 75 years of age with a weight of> 50 kg and a body mass index of 18 to 35 mg / m ² .

- familial or sporadic ALS;

Patients diagnosed with clinically feasible or definite ALS supported by an El Excorial standard (see Brooks BR., Et al., Eds. World Federation of Jeurology). Journal of the Neurological Sciences 1994; 124 (Suppl): 96-107;

- Duration of illness with symptom onset less than 36 months on screening;

- patients treated with stable doses of riluzole (100 mg / day) for at least 30 days prior to screening;

- Patients with a predicted normal value of FVC (mandatory vitality) of more than 60% for sex, height and age at screening visit;

- Patients with appropriate organ function at screening and baseline.

Key exclusion criteria :

- Patients who have undergone tracheostomy and / or gastrectomy.

Treatment management

The registered subjects were dosed during the meal, providing a total daily dose of 4.5 or 3 mg / kg muscle nip or matching placebo as indicated in Tables 2 and 3 below. In the morning dose, tablets were taken during meals. In the case of nausea, administration was carried out during lunch. For evening dose, tablets were taken during dinner.

A daily dose of 4.5 mg / kg of study treatment was administered in divided doses as indicated in Table 2.

[Table 2]

The dose (mg) of the study treatment administered according to the patient's body weight (4.5 mg / kg / day)

The daily doses of 3 mg / kg of study treatment were administered in divided doses as indicated in Table 3.

[Table 3]

The dose (mg) of the study treatment administered according to the patient's body weight (3 mg / kg / day)

Analysis Data Set :

Intention-To-Treat (ITT) Data Set - The ITT population is defined as any randomized patient who has or does not receive research treatment, or has at least one baseline efficacy assessment.

Modified Intent-To-Treat (mITT) data set - The mITT population is defined as all ITT patients with possible or defined amyotrophic lateral sclerosis taking at least one dose of the study procedure (muscle nip or placebo) .

Protocol-per-protocol (PP) data set - The PP population consists of all patients in the mITT population that do not have any major protocol deviations. This is a set of patients participating in the intended study. Patients terminating the study on the way are included in the PP population, unless there is a protocol deviation. Before locking the database, the exact reason for excluding patients from the PP population is fully defined and documented by the Data Review Committee.

Safety population - The safety population (SAF) consists of all enrolled patients taking at least one dose of study medication (muscle tissue or placebo).

Statistical method

Primary endpoint:

Change from baseline to 48 weeks in the modified amyotrophic lateral sclerosis functional assessment scale (ALSFRS-R).

Secondary endpoint:

The secondary analysis includes the following endpoints:

- progressive-survival (PFS), defined as ALSFRS-R or death at 9 points or more;

- Combination of function and survival (CAFS);

- survival defined as the time from the randomization until the date of the documented death or the first tracheotomy;

- time to first tracheotomy defined as the time from randomization to the first tracheotomy time;

- change in forced vitality (FVC) from baseline to each time point (4, 8, 12, 24, 36, 48 weeks);

- change from baseline to each point (4, 8, 12, 24 and 36 weeks) in ALSFRS-R;

- Survival rate defined as the percentage of patients who survived without tracheostomy at each time point (12, 24, 36, and 48 weeks).

Intermediate analysis

One intermediate analysis was designed for this study with approximately 50% of the randomized patients.

Intermediate analysis was performed without any non-blinded analysis. An independent contract research organization (CRO) has committed to conducting the analysis. The results were sent directly to the Independent Data Monitoring Committee (IDMC) members.

IDMC concluded that study AB10015 met its primary purpose based on a preliminary designed interim analysis. Three small teams were set up independently of the study run without access to the patient randomization list and collected top-line data.

Example 2

Clinical data indicate that marcotinib provides therapeutic benefits for very different subpopulations of ALS patients. These patients are identified as having a non-aggressive or moderately aggressive ALS (" normal moderator ") defined as an ALS patient with an ALSFRS-R score of less than 1.1 points per month prior to initiation of treatment.

Research AB10015 Intermediate analysis

Methods :

The study protocol and statistical analysis plan included provisions for analyzing the two subgroups of patients: "normal moderators" (patients with an ALSFRS-R score of less than 1.1 points per month prior to randomization, also non-aggressive Referred to as patients with moderate aggressive ALS) and " early moderators " (patients with an ALSFRS-R score of at least 1.1 points per month prior to randomization, also referred to as patients with aggressive ALS).

Research According to the AB10015 protocol, the interim analysis is scheduled to be performed after approximately 50% of the information is available for analysis. At the time of the interim analysis, 192 of the planned 381 patients (50%) randomized before February 12, 2015 were able to reach the 48th visit. These internal ITT populations consisted of 65, 64, and 63 patients randomized to placebo, marcitinib 4.5 mg / kg / day and marcitinib 3.0 mg / kg / day cohort, respectively. Of the 192 patients, 161 (85%) consisted of 54, 53, and 54 patients randomized to the placebo, marciti nip 4.5 mg / kg / day and marciti nip 3/0 mg / kg / It was a "normal host" patient. The randomization ratio according to the dose (3 mg / kg / day vs. 4.5 mg / kg / day) was 1: 1 (50%) and consequently the number of patients required for the interim analysis was the total number of patients, &Lt; / RTI &gt;

Intermediate analysis The primary endpoint is based on a change from baseline to 48 weeks in ALSFRS-R. The primary analysis was performed in the mITT "normal host" (ie non-aggressive or moderately aggressive ALS) subgroup. This analysis was performed on patients randomized to placebo (4.5 mg / kg / day) (group 1, n = 52) vs. placebo (group 3, n = 46) at 3.11% alpha-level. In the study visit, the loss value of ALSFRS-R was replaced based on the Modified Last Observation Carried Forward (mLOCF) method.

Absolute changes from baseline to 48 weeks in ALSFRS-R were assessed using an adjusted covariance analysis model (ANCOVA) for the following factors: treatment (marcitab or placebo), and ALS subgroup, Progression of ALSFRS-R score from symptom to baseline (point / month), ALSFRS-R score at baseline, prognosis (bulb vs. other), age at baseline; And geographic area.

The two-sided (1-alpha) confidence interval of the mean change difference between baseline and 48 hours was calculated between groups. The primary analysis used a re-randomization test. A re-randomization test (also referred to as a randomization test or a permutation test) obtains a distribution of test statistics under a null hypothesis by calculating all possible values of the test statistics under re-labeling of the observed data points Is a kind of statistical significance test. The percentage of repetitions where the p-value of the treatment factor was at least as small as the p-value of the treatment factor from the original data was calculated. At this rate, the observed p-value of the treatment factor is also considered as one replica in the molecule and denominator. This ratio is the p-value for the randomization test. When the randomized p-value was less than 3.11%, the hypothesis that there was no treatment difference was rejected at 3.11% level of significance.

To control the type I error rate of the entire family at the study level, the effect was analyzed in a phased manner (fixed array method). The fixed array method ensures that populations claimed and treated with selected doses are performed by adjusting the overall family error rate at the 0.0311 level for primary analysis. Array 1 was performed in a 4.5 mg / kg / day randomized " normal modulator " patient cohort. The primary analysis was an absolute change from the baseline to 48 weeks in the ALSFRS-R score (calculated using the "least squares mean" method). The analysis was considered to be crucial at the 0.0311 level of significance.

Results :

In general, patient demographics and baseline characteristics were well matched between treatment and subgroups. For the analysis of the effect of Machitinib therapy following the progression of the ALSFRS-R score in the different subgroups of non-aggressive or moderately aggressive ALS (ie, normal moderator) versus aggressive ALS (ie, early facilitator) .

i) ALSFRS-R (primary endpoint) change from baseline to 48 weeks in the 4.5 mg / kg / day randomized "normal moderator" patient cohort, according to the treatment group (versus placebo). This corresponds to arrangement 1 of the primary analysis of the intermediate analysis, the stepwise fixed array method.

A total of 98 patients were randomized to an assessable baseline and 48 weeks (n = 46) randomized to either the first set of mid-analysis primary endpoints, either marcitnib 4.5 mg / kg / &Lt; / RTI &gt; data from the &quot; normal modulator &quot; group with the data. In this cohort, mean exposure to maximal nasal mucositis (4.5 mg / kg / day) or placebo was 9.5 ± 2.8 months (range 1.7-11.5 months) and 9.3 ± 3.2 months (range 0.2-13.3 months), respectively.

Macit nip showed significant improvement compared to placebo at its primary endpoint and had an average reduction in ALSFRS-R of 14.51 points in patients treated with placebo compared to a decrease of 9.02 in patients treated with masitinib, P = 0.0032 (Table 4). Thus, muscleinib administered at 4.5 mg / kg / day produced a statistically significant delay in disease progression, as measured by the ALSFRS-R score in the ALS "normal modulator" subpopulation.

[Table 4]

A primary analysis of the "normal modulator" subgroup (ALSFRS-R score progression <1.1 point / month) comparing patients randomized to Machitinib 4.5 mg / kg / day with the placebo arm (intermediate AB10015)

^† Patient ^{assessable for} primary efficacy analysis. * P-values are based on re-randomization. The median level of significance was set at <0.0311. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

ii) from baseline to 48 weeks in a 4.5 mg / kg / day randomized patient cohort that directly compares the therapeutic effect between subgroups of the treated nasoconstituted nasotherapeutic " normal modulator " Changes in ALSFRS-R.

Masati Nib treatment of normal moderators (non-aggressive or moderately aggressive ALS) showed a strong statistically significant improvement in terms of ALSFRS-R scores compared to early-onset (aggressive ALS) patients, with 5.57 points of ALSFRS- R score decreased by 17.9 points versus the average decrease. Thus, marcotinib administered at 4.5 mg / kg / day had an unexpected effect on disease progression as measured by the ALSFRS-R score in the ALS "normal modulator" subgroup when compared to the ALS "early modulator" subgroup Generated a strong delay.

Unexpectedly, these data thus indicate that in the primary analysis, the proven positive therapeutic effect on versus placebo is strongly induced by the "normal host" subpopulation. Thus, mastitonib is highly effective in these subgroups of non-aggressive or moderately aggressive ALS patients (normal moderator), and less effective or limiting in aggressive ALS patients (early-onset).

[Table 5]

(4.5 mg / kg / day) comparing subgroups of "normal moderator" (progress of ALSFRS-R score <1.1 points / month) versus "early moderator" (progression of ALSFRS- A) Analysis of treated patients (median AB10015)

^† Patient ^{assessable for} primary efficacy analysis. The median level of significance was set at <0.0311. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol of 1. ^‡ absolute difference between delta = treatment group (normal host-early moderator). [CI] = (1-alpha) confidence interval. mITT population.

iii) Change in ALSFRS-R from baseline to week 48 in the 4.5 mg / kg / day randomized " early host " patient cohort, according to treatment group (versus placebo).

Observations that mastitonib had a limited effect in aggressive ALS patients (see Table 5, above) were performed at baseline in the 4.5 mg / kg / day randomized " early " patient cohort according to the treatment group It is confirmed by analysis of ALSFRS-R changes up to 48 hours.

There was no significant difference between the treatment groups in the "early-onset" subgroup. In fact, there was no delayed progression of disease progression in these patient populations (patients treated with Machitinib showed a larger mean decrease in ALSFRS-R score when compared to patients treated with placebo) (Table 6). This observation supports the unexpected result that masitinib is effective only in non-aggressive or moderately aggressive ALS patients (normal host) and supports the hypothesis that different mechanisms of disease progression contribute in part to the survival heterogeneity in the entire ALS population .

[Table 6]

Analysis of the "premature" subgroup (ALSFRS-R score progression ≥ 1.1 points / month) comparing randomized patients with placebo to 4.5 mg / kg / day versus placebo (median analysis AB10015).

^† Patient ^{assessable for} primary efficacy analysis. The median level of significance was set at <0.0311. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

Taken together, these data provide clinical benefits in a limited population of non-aggressive or moderately aggressive ALS (ie patients whose progression of the ALSFRS-R score before randomization is less than 1.1 points / month) Demonstrate unexpected superiority to other patient cohorts with aggressive ALS (i. E. Patients with a progression of the ALSFRS-R score before randomization &gt; = 1.1 points per month). These findings support the use of progression of ALSFRS-R scores prior to treatment initiation with thresholds of less than 1.1 points per month as independent predictors of maxillofacial treatment effect and patient selection among the entire ALS population.

Example 3

The final analysis of study AB10015 was performed when 100% of the information became available. Clinical data from this final analysis confirmed the discovery from AB10015 interim analysis, indicating that Machitinib provides a therapeutic benefit to very different subgroups of ALS patients. These patients are identified as being normal hosts defined as ALS patients (including non-aggressive and moderately aggressive ALS patients defined herein above) whose progression of the ALSFRS-R score before treatment initiation is less than 1.1 points per month.

Study AB10015 Final Analysis

The database cutoff was March 16, 2017. The data provided in this example was obtained in part from a preliminary analysis and itself represents the proximity to the last valid data set.

To measure the effect of masitinib on progression of the ALSFRS-R score in different subgroups of the entire ALS patient population, the following analyzes were performed.

i) ALSFRS-R (primary endpoint) change from baseline to 48 hours in the 4.5 mg / kg / day randomized patient cohort, according to the treatment group (versus placebo). This corresponds to the primary endpoint of the final analysis.

Maschinib administered at 4.5 mg / kg / day produced a statistically significant delay in disease progression, as measured by the ALSFRS-R score at the ALS "normal modulator" subgroup (<1.1 points / month) did. Macit nip showed significant improvement compared to placebo at its primary endpoint (P = 0.0142) and had an average reduction in ALSFRS-R score of -8.7 points vs. -12.1 points between marcitinib and placebo, respectively (3.4 Corresponding to the difference in points) (Table 7).

[Table 7]

A primary analysis (final AB10015) for the "normal modulator" subgroup (progression of the ALSFRS-R score below 1.1 points / month) comparing patients randomized to Machitinib 4.5 mg / kg / day versus placebo.

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

Considering the subgroup of "non-aggressive ALS" patients (<0.8 points / month), the mastitonib produced a delay of ALSFRS-R score corresponding to a difference of 3.4 points -8.3 points vs. -11.7 points) (Table 8).

[Table 8]

Primary endpoint analysis (final AB10015) for "non-aggressive" ALS subgroups (progression of the ALSFRS-R score below 0.8 points / month) comparing randomized patients with marciti nip 4.5 mg / kg / .

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

Considering the subgroup of "moderate aggressive ALS" patients (≥0.8 to <1.1 points / month), muscleitem resulted in a delay of ALSFRS-R score corresponding to a difference of 2.2 points -11 points versus -13.2 points) (Table 9). The cohort of patients with moderate aggressive ALS (progression of ALSFRS-R score of ≥ 0.8 to <1.1 points / month) was smaller than the cohort of patients with non-aggressive ALS (progression of ALSFRS-R score <0.8 points per month) .

[Table 9]

A primary analysis of "moderate aggressive" ALS subgroups (≥0.8 to <1.1 points / month progression of the ALS SFRS-R score) comparing randomized patients with marciti nip 4.5 mg / kg / day to placebo

^† Patient who can be evaluated for efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

Significant differences were not observed among the treatment groups of the "early-onset" subgroup (≥1.1 points / month), indicating that maximal nasal mucositis (4.5 mg / kg / day) had a limited effect on early- (See Table 10). In fact, there was no delayed disease progression in these patient populations. This observation supports the unexpected result that masitinib is effective only in normal modulator ALS patients (including non-aggressive ALS and moderately aggressive ALS subtype as defined herein above).

[Table 10]

Primary analysis (final AB10015) for the "early-stage" subgroup (≥1.1 points / month progression of the ALSFRS-R score) comparing patients randomized to marciti nip 4.5 mg / kg / day versus placebo.

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

Significantly, no significant difference (P = 0.11) was observed between the treatment groups in the entire study population (ie, cohort including normal and early-onset patients, regardless of progression of the ALSFRS-R score prior to treatment initiation) (Table 11). Thus, any study design based on the treatment of the entire ALS population could not demonstrate the therapeutic effect. This observation supports the unexpected result that maxillum is effective only in a limited subgroup of ALS patients and that identification of responding patients is indicative of new knowledge and can not be predicted by prior art teaching.

[Table 11]

The primary analysis (final AB10015) comparing randomized patients with placebo to the placebo group in the full study population "normal host and early host" (independent of the progression of the ALSFRS-R score)

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol 1. ^‡ the absolute difference between the treatment groups delta = (E City nip-placebo). [CI] = (1-alpha) confidence interval. mITT population.

ii) ALSFRS-R changes from baseline to week 48 in a 4.5 mg / kg / day randomized patient cohort that directly compares the efficacy of maxillum treatment among ALS subgroups.

MASTYNIP treatment of ALS patients showed a statistically significant treatment effect (P <0.001) in the ALSFRS-R score compared to the early-stage (aggressive ALS) patients (P <0.001) (Corresponding to a difference of 11.2 points) of the ALSFRS-R score of 8.4 points vs. 19.6 points (Table 12). Thus, Machitinib administered at 4.5 mg / kg / day had an unexpected, predictable, or predictable effect on disease progression as measured by the ALSFRS-R score in the ALS "normal modulator" subgroup when compared to the ALS " Generated a strong delay. Thus, muscleinib is highly effective in the " normal modulator " subgroup (including non-aggressive ALS and moderately aggressive ALS subgroup as defined herein above) and has ineffective or limited efficacy in early-onset ALS patients.

[Table 12]

Analysis of patients treated with masitinib (4.5 mg / kg / day) comparing subgroups of "normal moderator" versus "early moderator"

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. Town city nip (4.5) = 4.5 mg / kg / day town city nip + Li randomized groups received the rujol of 1. ^‡ absolute difference between delta = treatment group (normal host-early moderator). [CI] = (1-alpha) confidence interval. mITT population.

A similar statistically significant finding was that non-aggressive ALS patients (<0.8 points per month) versus aggressive ALS patients (≥1.1 points per month) (see Table 13) and non-aggressive ALS patients (<0.8 points per month) A comparison of moderate aggressive and aggressive ALS patients (≥ 0.8 points / month) (see Table 14).

[Table 13]

Analysis of patients treated with masitinib (4.5 mg / kg / day) comparing the subgroups of "non-aggressive" vs. "early (aggressive)

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. ^‡ Delta = absolute difference between treatment groups (normal moderator - early moderator). [CI] = (1-alpha) confidence interval. mITT population.

[Table 14]

Analysis of patients treated with masitinib (4.5 mg / kg / day) comparing the subgroups of "non-aggressive" versus "moderately aggressive + aggressive" (final AB10015)

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. ^‡ Delta = absolute difference between treatment groups (normal moderator - early moderator). [CI] = (1-alpha) confidence interval. mITT population.

Masati Nib treatment of moderate aggressive ALS patients (≥0.8 to <1.1 points / month) showed a strong trend of treatment effect in the ALSFRS-R score compared to aggressive ALS patients (≥1.1 points / month) (Table 15) ).

[Table 15]

Analysis of patients treated with masitinib (4.5 mg / kg / day) comparing the subgroups of "moderate aggressive" vs. "early (aggressive)" (final AB10015)

^† Patient ^{assessable for} primary efficacy analysis. The final level of significance was set at <0.05. Δ ALSFRS-R = Change from baseline to 48 weeks (least squares mean) in the ALSFRS-R score. ^‡ Delta = absolute difference between treatment groups (normal moderator - early moderator). [CI] = (1-alpha) confidence interval. mITT population.

In conclusion, these final analytical data from study AB10015 demonstrate that:

- Machitinib is an effective treatment for patients with ALS (group A is collectively referred to as non-aggressive or moderately aggressive ALS) with an ALSFRS-R score of less than 1.1 points per month prior to treatment initiation.

- Machitinib is most effective in the treatment of patients with an ALSFRS-R score of less than 0.8 points / month prior to initiation of therapy (this group is collectively referred to as non-aggressive ALS).

Patients with a progression of the ALSFRS-R score before initiation of treatment were ≥0.8 to <1.1 points per month (this group consisted of moderately aggressive ALS), although less than that for non-aggressive subgroups Quot;). &Lt; / RTI &gt;

- Machitinib is an ineffective treatment for ALS patients (group A is collectively referred to as aggressive ALS) whose progression of the ALSFRS-R score before treatment initiation is at least 1.1 points per month.

Claims (17)

Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, for use in the treatment of patients suffering from amyotrophic lateral sclerosis (ALS) with progression of the ALSFRS-R score before initiation of treatment is less than 1.1 points per month Lt; RTI ID = 0.0 &gt; tyrosine kinase &lt; / RTI &gt; 2. The inhibitor of claim 1, wherein the patient has a progression of the ALSFRS-R score less than 0.8 points / month prior to initiation of treatment. 2. The inhibitor of claim 1, wherein the patient has a progression of the ALSFRS-R score before initiation of treatment of less than 1.1 points per month and greater than or equal to 0.8 points per month (&gt; 0.8 to &lt; 1.1 points per month). 4. The inhibitor according to any one of claims 1 to 3, wherein the inhibitor is an inhibitor of mast cell activity. 5. The method of claim 4, wherein the mast cell inhibitor is selected from the group consisting of mastitinib, imatinib, cromolyn sodium, midosutaurin, BLU-285, conservinib, ibrutinib, LAS189386, DP-2618, Wherein the inhibitor is selected from the group consisting of salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, 5. The inhibitor according to any one of claims 1 to 4, wherein the inhibitor is an inhibitor of microglial cell activity. 7. The composition of claim 6, wherein the microglial cell inhibitor is selected from the group consisting of Machitinib, GW2580, Plexidarnib, BLZ945, Linipanib, OSI-930, Imatinib, Suminitinib, Nrotinib, Pasopapin, Wherein the inhibitor is selected from the group consisting of FPA008, quizarthinib, axitinib, motesanib, cediranip, JNJ-28312141, Ki-20227, MLN-518, sorafenib and SU-14813. 8. The inhibitor according to any one of claims 1 to 7, wherein the inhibitor is a 2-aminoaryl thiazole derivative. 9. The inhibitor according to any one of claims 1 to 8, wherein said inhibitor is mastitin or a pharmaceutically acceptable salt or solvate thereof, preferably mastitonib mesylate. 10. A pharmaceutical composition according to any one of claims 1 to 9, wherein the inhibitor, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably mastitonib mesylate, A dose in the range of 9.0 mg / kg / day (mg / kg body weight / day); Preferably at an initial dose of 3.0 mg / kg / day for at least 4 weeks followed by an initial dose of 4.5 mg / kg / day for at least 4 weeks and then 6.0 mg / kg / day, Provided is an inhibitor. 11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the inhibitor, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably the mastitonin mesylate is administered at a dose of 4.5 mg / kg / Day. &Lt; / RTI &gt; 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the inhibitor, preferably mastitinib or a pharmaceutically acceptable salt or solvate thereof, and more preferably a mastitonin mesylate is administered at a dose of 6 mg / kg / Day. &Lt; / RTI &gt; 13. The inhibitor according to any one of claims 1 to 12, wherein the inhibitor, preferably macitanium mesylate, is administered once a day by ingestion. 14. The inhibitor according to any one of claims 1 to 13, wherein the inhibitor, preferably macitanium mesylate, is orally administered. 15. An inhibitor according to any one of claims 1 to 14, wherein said inhibitor is administered in combination with at least one other pharmaceutically active ingredient. 16. The composition of claim 15, wherein said other pharmaceutically active ingredient is an inhibitor of an antglutamate compound, especially ryluzole, topiramate, gabapentin, lamotrigine, tamlan panel, ceftriaxone, glutamate carboxypeptidase II, Wherein said other pharmaceutically active ingredient is rilsuzole. An inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, for use according to any one of claims 1 to 16, Or a pharmaceutical salt or solvate thereof.